Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway

Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chondroitin sulfate proteoglycan (CSPG) interaction, plays a role in mDA neuron survival, function, and regeneration in PD. Our data show that inhibition of PTPRS using intracellular sigma peptide (ISP) enhances human mDA neuron neurite outgrowth in vitro, suggesting an inhibitory role of this receptor in the differentiation of human embryonic stem cell (hESC)-derived mDA neurons in vitro. However, genetic deletion and pharmacological inhibition of PTPRS does not affect mDA neuron survival, axon density, or motor behavior in 6-OHDA unilateral partially lesioned mice. Similarly, mDA-specific deletion of Ptprs does not affect the basal behavioral measurement in cKO mice, including general locomotion and motor learning. Interestingly, however, Ptprs deletion led to a reduced response in the behavior sensitization to repeated methamphetamine (METH) exposure in cKO mice, suggesting a dampened response in synaptic function in cKO mice under these conditions. Ex vivo voltammetry recording in the striatum indeed shows altered parameters of dopamine (DA) release upon stimulation. These findings indicate that the inhibition of PTPRS function in human mDA neuron progenitors might be a promising strategy for enhancing neurite outgrowth or incorporation in host tissues in transplantation therapies. Finally, our data support that inhibition of PTPRS function in mDA neurons in adult mice in vivo could inhibit METH induced plasticity and behavioral sensitization.